Alveolar Echinococcus in a 70-year-old man in Ontario

Abstract

Background:

Alveolar echinococcus, caused by the tapeworm Echinococcus multilocularis, mimics hepatic malignancy, and carries a mortality rate exceeding 90% in untreated patients.

Methods:

Diagnosis of E. multilocularis infection is established through clinical, radiographic, and microbiological assessments. Currently available laboratory diagnostics in Ontario are fresh tissue microscopy and histopathology. However, genus-specific Echinococcus enzyme-linked immunosorbent assay (ELISA) serology as well as confirmatory testing with species-specific serology and E. multilocularis polymerase chain reaction (PCR) can be obtained from external reference laboratories.

Results:

The article presents the first case report of human alveolar echinococcus in Ontario. We outline the multidisciplinary approach of diagnosis as well as surgical and medical management of E. multilocularis infection in a 70-year-old man in Ontario. We describe prior literature of alveolar echinococcus in Canadian settings and highlight its emerging nature with recent human case clusters in the Prairies and reports of E. multilocularis in recent veterinary literature in Ontario.

Conclusion:

E. multilocularis is an emerging parasitic infection in Canadian settings including Ontario. Clinicians should be aware of the emergence of this invasive infection, especially in those with close contact to canids.

Case Presentation

A 70-year-old man with right hip osteoarthritis was referred to hepatology clinic after incidental finding of a large subcapsular heterogeneous hepatic lesion on a CT scan of the abdomen and pelvis, performed to evaluate his right hip pain.

He was born in the United States and moved to Ontario over 30 years ago. His past medical history included melanoma that was resected 40 years prior with negative margins for extra-nodal involvement, and right hip osteoarthritis, with celecoxib as his only medication, used as per needed for hip pain. He had no family history of gastrointestinal malignancy or liver disease.

He was completely asymptomatic with the exception of right hip pain on exertion. His physical examination showed normal vital signs, mild hepatomegaly and no evidence of jaundice, abdominal tenderness, or chronic liver disease stigmata.

Liver enzymes and synthetic function including ALT, AST, ALP, GGT, albumin, INR, and total bilirubin were all within the normal range at his initial hepatology visit. His outpatient CT abdomen and pelvis demonstrated a 6.9 × 3.2 cm subcapsular hepatic mass (Figure 1) suspected to be a cholangiocarcinoma or potentially hepatocellular carcinoma. A follow-up abdominal ultrasound demonstrated a heterogeneously hyperechoic mass with no internal vascularity on Doppler to suggest neoplasm (Figure 2). Alpha-fetoprotein (AFP) and cancer antigens (CA) 19-9 were within normal limits.

Figure 1:

Axial and coronal post-contrast CT abdomen-pelvis, demonstrating a large hypoenhancing hepatic mass centred peripherally in segment 6 with irregular lobulated contours and capsular retraction on axial plane (green arrow).

There is linear invasion along a segmental portal vein branch on coronal plane (yellow arrow). The finding simulates a large aggressive primary or secondary hepatic malignancy with vascular invasion

Figure 2:

Grey mode and Doppler abdominal ultrasound images demonstrate a heterogeneously hyperechoic mass with internal hypoechoic to anechoic small cystic-appearing foci in liver segment 6.

Doppler images demonstrate no significant internal vascularity to suggest solid neoplasm. Extension into a segmental portal vein branch is again seen (yellow arrow)

Biopsy of the liver lesion demonstrated necrotizing granulomatous inflammation with a negative acid-fast bacilli (Ziehl-Neelsen) stain but strongly positive gomori methenamine silver (GMS)-stained laminated membranes, suggestive of echinococcal infection, and without any features of malignancy (Figure 3).

Figure 3:

Histopathology of liver tissue from resection with hematoxylin and eosin (H&E) stain showing necrotizing granulomatous inflammation.

(a) Low power magnification showing echinococcal cyst with adjacent liver. (b) High power magnification showing echinococcal cyst with laminated membranes. (c) High power magnification showing granulomatous reaction at interface between echinococcal cyst and adjacent liver

Following liver biopsy result, the patient was re-evaluated by hepatology and referred to infectious diseases (ID). Upon ID assessment, the patient reported encountering coyotes and foxes along hiking trails in York Region, however he did not have direct physical contact with these animals on these trails. His dog accompanied him off-leash and very likely came in contact with mice or other rodents as well as canids or their feces on these trails. Furthermore, 3 years ago, while he was visiting his sister on a farm in Connecticut, USA, he had buried a fox that was killed by a relative for stealing chickens from the farm.

His infectious work-up revealed a positive Echinococcus spp IgG enzyme immunoassay (EIA) serology with an index of 2.48 (reference: non-reactive <0.9, reactive ≥1.1). Given his serology results, multiple exposures to coyotes and foxes, the radiographic liver appearance, and liver biopsy results, the diagnosis was concluded to be hepatic alveolar echinococcus (Echinococcus multilocularis) infection. The patient was subsequently started on oral albendazole (400 mg twice daily) and referred to hepatobiliary surgery. He then underwent complete resection of the hepatic mass with intraoperative findings of spongy irregular vesicles infiltrating the liver parenchyma that are characterstic of alveolar echinococcus. (Figure 4).

Figure 4:

Intraoperative findings of characteristic alveolar appearance of Echinococcus multilocularis with multiple different-sized vesicles (or “locules”) infiltrating liver parenchyma

Serology was sent to the Institute for Infectious Diseases (IFIK) in Bern, Switzerland for further speciation and was confirmed as E. multilocularis using species-specific EIA and Western blot. The liver tissue was sent to Alberta's Public Health Laboratory for research-use only PCR which also returned positive for E. multilocularis. The patient was discharged 2 days after surgery with no postoperative complications. He was continued on albendazole with a plan to treat for a minimum of 2 years, with positron emission tomography (PET) scan at 6 months to monitor for recurrence.

Discussion

Echinococcus is a tapeworm that typically infect canines such as dogs, coyotes, foxes, and wolves (1). The majority of human cases worldwide are due to the E. granulosus sensu lato complex and known as cystic echinococcosis (2). Human cases of E. multilocularis, also known as alveolar echinococcosis, are less frequently reported with recent annual estimates of 18,000 cases globally, yet these carry significant mortality risk (3,4).

E. multilocularis is a small cestode characterized with an alveolar like structure of several vesicles at its metacestode stage (5). It typically measures 1–4 mm and can proliferate up to 15–20 cm in diameter in human hosts (4,5).

The adult form of E. multilocularis resides within the small intestine of definitive hosts, most often canid species (6). The definitive host excretes eggs in their stool, which are then consumed by rodents. Infected rodents develop hydatid cysts, which are then consumed by the definitive host, completing the life cycle of the parasite. Humans acquire the infection as accidental intermediate hosts if ingesting the eggs excreted by the definitive host, either directly or indirectly from the environment (6). Because eggs may stick to the fur of animals, humans can also acquire the infection from petting dogs with E. multilocularis then accidentally ingesting eggs from contaminated hands (1,6). Given its mode of transmission, when alveolar echinococcosis is suspected, it is prudent to assess for both domestic and wild animal exposures, particularly with dogs, foxes, and coyotes (3).

E. multilocularis infections have mainly been localized in Asia, Europe, and North America (5). Cases from China are thought to represent the majority of the global burden of E. multilocularis infection (3). The first human case of E. multilocularis in Canada was reported in Manitoba in the 1930s (7). Since then, human clusters of E. multilocularis have been described in Alberta, Saskatchewan, and Manitoba (1,3,8).

Four cases of alveolar echinococcosis in Ontario were estimated between 2001 and 2014 based on hospital discharges with International Classification of Diseases version-9 (ICD-9) code (3). Since its mandatory provincial public health reporting in 2018, an additional three cases (including this presented case) of confirmed human E. multilocularis infection have been reported in Ontario thus far (unpublished data), although these cases may or may not have been locally acquired. Given our patient's history of multiple exposures to coyotes and foxes on Ontario hiking trails throughout the last two decades, rather than a one-time contact with fox in Connecticut, USA, 3-years prior to diagnosis, local acquisition in Ontario is suspected to be more likely. Furthermore, E. multilocularis has a marked latency period with incubation period often ranging from 5 to 15 years. Therefore, acquisition of infection in Connecticut, a state with no prior reported cases of human alveolar echinococcus, is thought to be unlikely given timeline of his diagnosis with a 7-cm hepatic lesion 3 years later (6). Molecular genotyping of E. multilocularis strain is currently underway for confirmation of local acquisition in this case.

Recent veterinary literature has highlighted the regional emergence of E. multilocularis, with identification of E. multilocularis DNA in 23% of fecal material isolated from 460 wild canids in Ontario (9). Given that this canid E. multilocularis prevalence was reported in the western-central region of the province, a region with dense human population, zoonotic transmission is likely underreported. Increasing human prevalence maybe related to urbanization and subsequent closer human contact with wildlife as well as introduction of more virulent European-like strain as described in western Canada (9,10).

The infection has a predilection to the right lobe of liver, as was the case for our patient, but can infect any other organ as well. It can manifest as one or multiple cystic lesions measuring many centimetres in diameter and mimicking hepatic neoplasms (2,6). Patients present with a range of symptoms, from incidental asymptomatic identification to abdominal pain, fatigue, weight loss, jaundice, or other manifestations depending on the organ infected (6,11). A high index of suspicion is required to make this diagnosis and patients often undergo repeat biopsy prior to diagnosis (12). The primary lesion can spread locally via organ infiltration and may also metastasize to distant sites (eg, lungs or brain) via blood and lymphatic spread (2,6). Patients with untreated hepatic infections may develop hepatic failure with greater than 90% mortality rates over 15 years (6).

Imaging is a key modality of E. multilocularis diagnosis. Ultrasound is recommended by the World Health Organization (WHO) as the imaging technique of choice. It identifies characteristic tumour-like mass with intermixed hypoechoic and hyperechoic areas along with irregular calcifications dispersed randomly (2,6). Other findings include a large central necrotic area surrounded by hyperechoic rings (11). CT and MRI can be used to better characterize findings such as calcification patterns and multivesicular morphology respectively (11) and can better appreciate the degree of invasion to surrounding tissue (6). When a lesion is strongly suspected, additional imaging such as pulmonary and brain imaging, is recommended to help rule out other potential foci of infection (6).

Laboratory diagnosis of E. multilocularis in Ontario is mostly supported by fresh tissue microscopy, histopathology, and serology. Protoscolices and hooklets are seen in <50% of cases, limiting fresh tissue microscopy. Histopathology findings for E. multilocularis infection are cysts with central necrotizing granulomatous inflammation and lined with laminated membranes that stain strongly positive with GMS or periodic acid-Schiff (PAS), as seen in our patient (8,11). Furthermore, intraoperative gross visualization of multiple alveolar vesicles (also referred to as “locules”) of E. multilocularis offers supportive evidence of diagnosis (6). Serology can be tested at the National Reference Centre for Parasitology with a genus-specific Echinococcus enzyme-linked immunosorbent assay (ELISA) and, if requested by the submitter, it is also forwarded to IFIK for species-specific E. multilocularis EIA and western blot assays. At time of writing, PCR for human infections is not currently validated in Ontario but can be performed upon request to assist in investigations.

The ideal treatment for E. multilocularis infections is surgery with complete resection of primary lesion, however this is not always possible given significant delays in disease detection and distant spread at the time of diagnosis (11). Medical therapy with albendazole 10–15 mg/kg/day often given as 400 mg twice daily, should be initiated peri-operatively and is generally continued for at least 2 years after complete resection (11). Treatment recommendations are primarily derived from expert consensus and data on second-line pharmacotherapy options is limited to animal models, in vitro studies and case series (11,13). WHO classification of disease through assessment of parasitic mass in liver, spread to neighboring organs and distant metastasis (PNM) can be used to guide duration of benzimidazole therapy (11). Life expectancy with effective treatment can improve to 20 years from diagnosis compared to only 3 years in untreated cases (11). For patients in whom complete resection of the primary lesion is not achieved, albendazole therapy would be lifelong (11). Potential side effects of albendazole include gastrointestinal upset, headaches, alopecia, leukopenia, and drug-induced liver injury (13). Given severity of side effects, particularly with hepatotoxicity and myelosuppression, albendazole therapeutic drug level monitoring (TDM) should be considered. Although albendazole TDM is available in Alberta Public Health Laboratory, it is not available in Ontario at the time of writing (14,15).

Another important consideration for albendazole use, particularly in Canada, is its limited accessibility as the medication has not been approved for human use by Health Canada (16). Therefore, clinicians need to apply to the Special Access Program (SAP) for compassionate access of this drug. In addition to initial delays of treatment while awaiting SAP approval of albendazole, clinicians are also tasked with reapplying to SAP every 6 months for further supply of the drug throughout the treatment course which often ranges from 2 years to lifelong (17).

E. multilocularis is an emerging parasitic infection in many Canadian settings including Ontario. Imaging findings of E. multilocularis mimic cholangiocarcinoma and Canadian clinicians should be aware of this potential infection, especially in those with close contact to canids. Multidisciplinary care with involvement of infectious diseases, medical microbiology, hepatology, and hepatobiliary surgery is instrumental in effective diagnosis and management of this invasive infection.

Acknowledgements:

The authors would like to acknowledge Dr. Kinga Kowalewska-Grochowksa, Dr. Kai Duan, Dr. Sandra Fischer, and Dr. Zersenay Alem for their insightful input on this manuscript.

Contributors:

Conceptualization, RT Zewude, A Corbeil, S Fung, I Bogoch; Methodology, RT Zewude, C-A Moulton, I Bogoch; Software, A Corbeil; Formal Analysis, RT Zewude, I Bogoch; Investigation, RT Zewude, A Corbeil, S Fung, C-A Moulton, I Bogoch; Resources, RT Zewude, A Corbeil, S Fung, C-A Moulton, I Bogoch; Data Curation, RT Zewude, A Corbeil, S Fung, C-A Moulton, I Bogoch; Writing – Original Draft, RT Zewude, A Corbeil, S Fung, I Bogoch; Writing – Review & Editing, RT Zewude, A Corbeil, S Fung, C-A Moulton, I Bogoch; Visualization, RT Zewude, A Corbeil, S Fung; Supervision, S Fung, C-A Moulton, I Bogoch; Project Administration, RT Zewude, I Bogoch

Ethics Approval:

Ethics approval was not required for this article.

Informed Consent:

The authors confirm that informed patient consent has been secured from all patients.

Registry and the Registration No. of the Study/Trial:

N/A

Funding:

No funding was received for this work.

Disclosures:

IIB consults to BlueDot, a social benefit corporation tracking emerging infectious diseases, and to the NHL Players’ Association.

Peer Review:

This manuscript has been peer reviewed.

Animal Studies:

N/A